Healthy
Conditions
Keywords
Pharmacokinetics, Safety
Brief summary
The purpose of this study is to characterize and compare the concentration-time profiles and multiple dose pharmacokinetics of a 5 minute intravenous (IV) bolus of ertapenem 1 gram daily versus the standard 30 minute infusion in healthy volunteers. Safety and tolerability and pharmacodynamic target attainment using Monte Carlo simulation will also be assessed and compared.
Interventions
DRUGertapenem
1 gram IV bolus every 24 hours (q24h) for 3 days
Sponsors
Merck Sharp & Dohme LLC
Hartford Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Healthy adults (18 years of age or older)
Exclusion criteria
* Ertapenem or other beta-lactam allergy * Pregnant or breast feeding females * Body Mass Index (BMI) greater than or equal to 30 * Abnormal lab values at baseline * Hypertension * Significant medical abnormality * Regular alcohol consumption * Significant nicotine use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) at Steady-State (After 3rd Dose) | 5 or 30 minutes post start of infusion on Day 3 | Cmax is measured at 5 minutes after the beginning of the infusion for the 5 minute IV bolus dosage regimen and at 30 minutes after the beginning of the infusion for the 30 minute infusion dosage regimen. |
| Area Under the Curve From 48 to 72 Hours [AUC(48-72)] | 0-24 hours after 3rd ertapenem dose | AUC(48-72) is the 24 hour area under the concentration versus time curve after the 3rd dose of ertapenem, which is selected to measure approximate AUC at steady-state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 3 days | The following laboratory assessments will be make before and after participation in the study to determine if objective changes occurred: blood pressure, pulse rate, temperature, complete blood count with differential, platelet count, blood urea nitrogen, serum creatinine, liver function panel \[aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase\], total bilirubin, and urinalysis with microscopy. Monitoring of other pathologic or unintended changes in structure (signs),or function (symptoms) of the body associated with participation in the study will occur. |
| Probability of Target Attainment (PTA) | Simulated Steady-State Exposure | After simulating 5000 patients receiving each dosing regimen, the probability of achieving free drug concentrations above an MIC of 0.25 mcg/mL and 0.5mcg/mL for at least 40% of the dosing interval (40% fT\>MIC) is calculated at each MIC dilution. |
Countries
United States
Participant flow
Recruitment details
Healthy adult volunteers were recruited in August/September 2010.
Pre-assignment details
The target enrollment of 12 volunteers was met. All 12 participants completed at least one phase of the study, while 11 completed the entire study.
Participants by arm
| Arm | Count |
|---|---|
| Ertapenem IV 5 Minute Bolus First, Then 30 Minute Infusion Participants received ertapenem 1 gram as a 5 minute IV bolus every 24 hours for 3 doses. After a 4 day washout, participants were crossed over to receive ertapenem 1 gram as a 30 minute IV infusion every 24 hours for 3 doses. | 11 |
| Ertapenem IV 30 Minute Infusion First, Then 5 Minute Bolus Participants received ertapenem 1 gram as a 30 minute infusion every 24 hours for 3 doses. After a 4 day washout, participants crossed over to receive ertapenem 1 gram as a 5 minute IV bolus every 24 hours for 3 doses. | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Ertapenem IV 30 Minute Infusion First, Then 5 Minute Bolus | Ertapenem IV 5 Minute Bolus First, Then 30 Minute Infusion | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 11 Participants | 23 Participants |
| Age Continuous | 32.4 years STANDARD_DEVIATION 13.9 | 32.4 years STANDARD_DEVIATION 13.9 | 32.4 years STANDARD_DEVIATION 13.9 |
| Region of Enrollment United States | 12 participants | 11 participants | 23 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 11 | 9 / 12 |
| serious Total, serious adverse events | 0 / 11 | 0 / 12 |
Outcome results
Primary
Area Under the Curve From 48 to 72 Hours [AUC(48-72)]
AUC(48-72) is the 24 hour area under the concentration versus time curve after the 3rd dose of ertapenem, which is selected to measure approximate AUC at steady-state.
Time frame: 0-24 hours after 3rd ertapenem dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertapenem 1 Gram IV 5 Minute Bolus | Area Under the Curve From 48 to 72 Hours [AUC(48-72)] | 561.17 mcg*hr/mL | Standard Deviation 77.01 |
| Ertapenem 1 Gram IV 30 Minute Infusion | Area Under the Curve From 48 to 72 Hours [AUC(48-72)] | 531.32 mcg*hr/mL | Standard Deviation 56.86 |
Primary
Maximum Observed Plasma Concentration (Cmax) at Steady-State (After 3rd Dose)
Cmax is measured at 5 minutes after the beginning of the infusion for the 5 minute IV bolus dosage regimen and at 30 minutes after the beginning of the infusion for the 30 minute infusion dosage regimen.
Time frame: 5 or 30 minutes post start of infusion on Day 3
Population: Each participant received ertapenem as a 5 minute infusion and as a 30 minute infusion, only in different order due to cross-over design. Data for all participants receiving each dosage regimen are included in each arm for results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertapenem 1 Gram IV 5 Minute Bolus | Maximum Observed Plasma Concentration (Cmax) at Steady-State (After 3rd Dose) | 193.33 mcg/mL | Standard Deviation 43.27 |
| Ertapenem 1 Gram IV 30 Minute Infusion | Maximum Observed Plasma Concentration (Cmax) at Steady-State (After 3rd Dose) | 165.70 mcg/mL | Standard Deviation 20.38 |
Secondary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
The following laboratory assessments will be make before and after participation in the study to determine if objective changes occurred: blood pressure, pulse rate, temperature, complete blood count with differential, platelet count, blood urea nitrogen, serum creatinine, liver function panel \[aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase\], total bilirubin, and urinalysis with microscopy. Monitoring of other pathologic or unintended changes in structure (signs),or function (symptoms) of the body associated with participation in the study will occur.
Time frame: 3 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertapenem 1 Gram IV 5 Minute Bolus | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 10 participants |
| Ertapenem 1 Gram IV 30 Minute Infusion | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 9 participants |
Secondary
Probability of Target Attainment (PTA)
After simulating 5000 patients receiving each dosing regimen, the probability of achieving free drug concentrations above an MIC of 0.25 mcg/mL and 0.5mcg/mL for at least 40% of the dosing interval (40% fT\>MIC) is calculated at each MIC dilution.
Time frame: Simulated Steady-State Exposure
Population: The probability of achieving 40% T\>MIC is reported at a MIC of 0.25mcg/mL and 0.5mcg/mL respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ertapenem 1 Gram IV 5 Minute Bolus | Probability of Target Attainment (PTA) | PTA at 0.25 | 97.0 % of 5000 simulated patients |
| Ertapenem 1 Gram IV 5 Minute Bolus | Probability of Target Attainment (PTA) | PTA at 0.5 | 1.7 % of 5000 simulated patients |
| Ertapenem 1 Gram IV 30 Minute Infusion | Probability of Target Attainment (PTA) | PTA at 0.25 | 97.9 % of 5000 simulated patients |
| Ertapenem 1 Gram IV 30 Minute Infusion | Probability of Target Attainment (PTA) | PTA at 0.5 | 2.8 % of 5000 simulated patients |